The purpose of this project is to demonstrate the feasibility to detect organ-specific mutagenic responses to a variety of chemical compounds in relation to organ-specific carcinogenic action. A transgenic mouse model was constructed carrying multiple copies of a plasmid, containing the bacterial lacZ marker gene, integrated head-to-tail in the genome of all organs and tissues. Highly efficient protocols for the rescue of these vectors from their integrated state have been developed. The detection of mutations in the lacZ reporter gene is facilitated by a positive selection system. The use of this novel lacZ plasmid--based transgenic mouse model makes it now possible to study DNA damage and mutant induction in the same animal and in the same organ after treatment with low doses of a particular carcinogenic agent. This new in vivo transgenic mouse mutagenicity assay provides an unique opportunity to study the induction of tissue-specific mutations that reflect the integration of pharmacokinetics, biotransformation, DNA repair responses, and tissue susceptibility. PROPOSED COMMERCIAL APPLICATION: The development of new drugs and chemicals by pharmaceutical and chemical industries requires that the safety of these new compounds is evaluated as regards to their potential Toxic effects. The transgenic mouse mutation assay, as described in this project, is expected to become a standard tool in toxicology testing by industry, third-party agencies and medical schools and universities involved in toxicological testing and cancer risk assessment. As such, this new assay has great commercial potential.